Krüppel-Like Factor 8 (KLF8) Is Expressed in Gliomas of Different WHO Grades and Is Essential for Tumor Cell Proliferation

Abstract

Krüppel-like factor 8 (KLF8) has only recently been identified to be involved in tumor cell proliferation and invasion of several different tumor entities like renal cell carcinoma, hepatocellular carcinoma and breast cancer. In the present study, we show for the first time the expression of KLF8 in gliomas of different WHO grades and its functional impact on glioma cell proliferation. In order to get information about KLF8-mRNA regulation qPCR was performed and did not reveal any significant difference in samples (n = 10 each) of non-neoplastic brain (NNB), low-grade gliomas (LGG, WHO°II) and glioblastomas (GBM, WHO°IV). Immunohistochemistry of tissue samples (n = 7 LGG, 11 AA and 12 GBM) did not show any significant difference in the fraction of KLF8-immunopositive cells of all analyzed cells in LGG (87%), AA (80%) or GBM (89%). Tissue samples from cerebral breast cancer metastasis, meningiomas but also non-neoplastic brain demonstrated comparable relative cell counts as well. Moreover, there was no correlation between KLF8 expression and the expression pattern of the assumed proliferation marker Ki67, which showed high variability between different tumor grade (9% (LGG), 6% (AA) and 15% (GBM) of Ki67-immunopositive cells). Densitometric analysis of Western blotting revealed that the relative amount of KLF8-protein did also not differ between the highly aggressive and proliferative GBM (1.05) compared to LGG (0.93; p<0.05, studens t-test). As demonstrated for some other non-glial cancer entities, KLF8-knockdown by shRNA in U87-MG cells confirmed its functional relevance, leading to an almost complete loss of tumor cell proliferation. Selective blocking of KLF8 might represent a novel anti-proliferative treatment strategy for malignant gliomas. Yet, its simultaneous expression in non-proliferating tissues could hamper this approach.

p75 Neurotrophin Receptor Cleavage by α- and γ-Secretases Is Required for Neurotrophin-mediated Proliferation of Brain Tumor-initiating Cells

“…Ki67 is a nuclear protein highly linked with cell proliferation and extensively used as a proliferation marker in human tumors (34,35). Following p75NTR knockdown by two p75NTR-siRNAs, there was a decrease in the proliferation rate of BTICs in vitro (Fig.…”

Krüppel-like factor 8 induces epithelial-to-mesenchymal transition and promotes invasion of pancreatic cancer cells through transcriptional activation of four and a half LIM-only protein 2

“…As a GT-box (CACCC) binding dual-transcription factor, KLF8 regulates the transcription of numerous genes by recruiting the C-terminal binding protein (CtBP) corepressor (6-10) or p300 and P300/CtBP-associated factor histone acetyltransferase co-activators (8,(11)(12)(13)(14) in order to target gene promoters. It is aberrantly overexpressed in a number of cancer subtypes and has been implicated in the initiation, development and progression of these cancer subtypes, including hepatocellular carcinoma (15)(16)(17), gastric cancer (18)(19)(20)(21), breast cancer (22,23), ovarian cancer (14,24), renal cancer (22,25) and glioma (26). It is worth noting that KLF8 induced tumor cell epithelial-to-mesenchymal transition (EMT) and maintained the invasive potential of cancer, which appeared to serve a critical role in the metastatic progression of cancer cells (6,27).…”

Generation of Mice Deficient in both KLF3/BKLF and KLF8 Reveals a Genetic Interaction and a Role for These Factors in Embryonic Globin Gene Silencing

“…In addition, KLF8 has been shown to activate transcription from some gene promoters (21)(22)(23)(24). KLF8 is not expressed at readily detectable levels in most cell and tissue types studied to date (55), but numerous studies have reported its upregulation in various human cancers, including prostate (56), gastric (57,58), hepatocellular (59,60), glioma (61), breast (62,63), renal (64), and ovarian (65). KLF8 has been shown to regulate oncogenesis by promoting cellular proliferation and tumor invasion and by inhibiting apoptosis (21,(65)(66)(67)(68) Crossing these mice with Klf3 null mice results in embryonic lethality, indicative of a genetic interaction between these two factors.…”